Thrombotic Thrombocytopenic Purpura

Serena Ezzeddine Morning Report September 8, 2008

Epidemiology
Suspected TTP-HUS- 11cases/million/yr Idiopathic TTP-HUS- 4.5 cases/million/yr Severe ADAMTS13 deficiency- 1.7 cases/million/yr Incidence rates were greater for women and African-Americans Prior to plasma exchange, mortality rate was as high as 90%, now less than 20%

Terminology

TTP and HUS (hemolytic uremic syndrome) are both acute syndromes with abnormalities in multiple organ systems and evidencing microangiopathic hemolytic anemia and thrombocytopenia. Although some studies appear to distinguish these two entities the presenting features are essentially the same in most adult patients. Furthermore, the pathologic changes are the same and so is the initial treatment.

Definitions and Diagnosis

The Classic Pentad of TTP

Microangiopathic hemolytic anemia Thrombocytopenia Renal insufficiency or abnormalities Neurologic abnormalities that can be fluctuating Fever

Most common symptoms at presentation are nonspecific and include abdominal pain, nausea, vomiting and weakness.

Definitions and Diagnosis

In the era before effective treatment, it was common for all five features of the pentad to be present, but now it is rare for all to be present in same patient. Now, only thrombocytopenia and microangiopathic hemolytic anemia WITHOUT another clinically apparent cause is required to suspect TTP-HUS and initiate treatment.

Definitions Continued

MAHA-nonimmune hemolysis (negative coombs) with prominent red cell fragmentation (schistocytes) on peripheral blood smear. Will exhibit increased LDH and indirect bili. Schistocytes-in the appropriate clinical setting schistocyte count>1% was strongly suggestive of TTPHUS, ie 2 or more schistos in microscopic field at 100x magnification. Thromoboctyopenia- mean in a series was 25,300 prior to treatment. Renal disease- due to renal thrombotic microangiopathy, which is usually associated with a UA that is often near normal with only mild proteinuria (between 1-2 g/day) and few cells or casts

Definitions Continued
Neurologic symptoms - most are subtle, such as transient confusion or severe headache. Focal, objective abnormalities are less common, but grand mall seizures and coma can occur. Fever- less frequent finding, but the presence of chills and high spiking fever should suggest dx of sepsis or DIC. Cardiac involvement- incidence is difficult to determine, but diffuse platelet thrombi and associated hemorrhage in cardiac tissues can lead to arrythmias, MIs, sudden death, shock, or heart failure.

SCHISTOCYTES!

Pathophysiology and ADAMTS13

Before 1998, there was a lack of knowledge of the pathophysiology of TTP. In that year, adults with idiopathic TTP were reported to have acquired antibodies that inhibit VWF cleaving protease, which is normally present in plasma. In 2001, VWF cleaving protease was purified and cloned by several groups, shown to be a new member of the a disintegrin and metalloprotease with thrombospondin type 1 repeats-aka ADAMTS13. In initial studies with Furlan et al, in 1997, no inhibitor of the enzyme was found, and the deficiency was ascribed to an abnormality in the production, survival or function of protease, but then in 1998, concomitant studies showed that the protease activity was decreased during acute episode of TTP, but returned to normal in recovery, so there was a transient autoantibody produced against the enzyme during acute episodes.

Pathogenesis

VWF is synthesized in endothelial cells and assembled in large multimers that are present in normal plasma. The large multimers, ie unusually large von willebrand factor (ULVWF) are rapidly degraded in the circulation into normal size range of VWF multimers by ADAMTS13. ADAMTS13 deficiency could lead to accumulation of ULVWF multimers, platelet aggregation, and platelet clumping. ULVWF multimers accumulate in patients with TTP being found in platelet thrombi and serum. The ULVWF can attach to activated platelets thereby promoting aggregation.

Figure 1. Pathogenesis of idiopathic thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 deficiency

Sadler, J. E. Hematology 2006;2006:415-420

Copyright 2006 American Society of Hematology. Copyright restrictions may apply.

ADAMTS13
An inhibitory autoantibody to ADAMTS13 has been found at varying titers among high percentage of patients with idiopathic TTP who have severe ADAMTS13 deficiency, and the inhibitory IgG is directed at various elements of the protease. It has been suggested that levels of ADAMTS13 less than 5% with or without an inhibitor antibody may be part of a larger autoimmune response. Non-inhibitory antibodies to ADAMTS13 have also been demonstrated.

ADAMTS13 and prognosis

So usually, in acute idiopathic TTP, there is a severe deficiency in ADAMTS13 activity (undetectable or <5%), although senstivity/specificity remains controversial. Severe deficiency is less common in secondary TTP. For most patients, a complete response to plasma exchange is accompanied by normalization of ADAMTS13 activity and disappearance of inhibitors, if present. Persistently undetectable ADAMTS13 in plasma during remission was found to be highly predictive of recurrence, and also the higher the antibody titers, clinical manifestations were more severe and responses to plasma exchange were delayed

Treatment

PLASMA EXCHANGE -do NOT wait!

Usually done daily until platelet count has normalized (150K for 2 days) and hemolysis has largely ceased, ie normalized LDH. Exchange 1 to 1.5 plasma volumes daily 1/3 to of patients have prompt exacerbation of thrombocytopenia and hemolysis when plasma exchanged stopped or tapered. In these cases re-institute daily exchange, or even twice daily exchange with a planned tapering schedule

Plasma Exchange continued

Serial observations indicate that neurologic symptoms and serum LDH improve first, then platelet count, and improvement of renal function also occurs but is unpredictable FFP is used usually four units per liter plasma removed. Most commonly used. Cryo-poor plasma (VWF largely removed), but can lead to deficiency of fibrinogen and Factor VIII Plasma infusion without exchange can serve as emergencv treatment if exchange not readily available.

Treatment
Corticosteroids (prednisone 1mg/kg) or methylprednisolone 125mg IV BID) either adjunctively immediately or if platelet counts do not increase within several days of plasma exchange, or if thrombocytopenia recurs when plasma exchange treatments are diminished or stopped. There is little evidence for this strategy, but is used on the justifiable assumption that TTP is immune mediated.

Treatment

RITUXIMAB

Humanized monoclonal antibody against CD20, which is expressed on B cells, and it rapidly clears B cells from circulation, preventing replenishment of pathological plasma cells. Remission associated with disappearance of ADAMTS13 inhibitors and normalization of activity levels Should be considered in TTP patients who fail to respond to daily PE and corticosteroids after 7-14 days Dose 375 mg/m2 IV qweek for minimum of four weeks and maximum of 8 weeks.

TTP and Lupus

TTP is a known complication in SLE and 1-4% of patients with SLE may experience an episode of TTP during their life. Possibly, the occurrence of TTP in SLE pts is underestimated because of overlapping symptoms In vast majority of SLE-related TTP, SLE dx first, 13-15% TTP dx first, and 12-26% dx concomitantly Pts with active vasculitis esp with severe HTN and renal involvement may be difficult to distinguish from ITTP, and may represent true overlap syndrome between TTP and SLE.

TTP and SLE

References

NEJM 2006; 354:1927-35 George, James MD-Thrombotic Thrombocytopenic Purpura. Uptodate. Diagnosis, Causes, and Treatment of TTP-HUS Hematology 2004:407-423.Recent Advances in Thrombotic Thrombocyotopenic Purpura, Sadler Et al Hematology 2007. TTP and ADAMTS13: When is testing appropriate? Mannucci et al Hematology 2006.Thrombocytopenic Purpura:A moving Target. Sadler Hoffman:Hematology: Basic Principles and Practice fourth edition. Chapters 42 and 132 Swiss Med Wkly 2007;137:518-524. Rituximab for acute plasma refractory thrombotic thrombocyotopenic purpura. Eur J Haematology 2005;75:436-440. Acquired TTP as presenting symptom of SLE. Successful treatment with plasma exchange and immunosuppression-report of 2 cases Blood cells, Molecules and Diseases (2002) 28(3) May/June:385-391. Ritux Therapy for Refractory TTP Thrombotic Thrombocytopenic Purpura and Systemic Lupus Erythematous:Distinct entities or overlapping syndromes. Internet Journal of Internal Medicine; Cheung